Symmetrical bis(heteroarylmethoxyphenyl)alkylcarboxylic acids as inhibitors of leukotriene biosynthesis

Article abstract of DOI:10.1021/jm000180n

Symmetrical bis(quinolylmethoxyphenyl)alkylcarboxylic acids were investigated as inhibitors of leukotriene biosynthesis and 4,4-bis(4-(2-quinolylmethoxy)phenyl)pentanoic acid sodium salt (47·Na) met our design parameters for a drug candidate (ABT-080). This compound was readily synthesized in three steps from commercially available diphenolic acid. Against intact human neutrophils, 47·Na inhibited ionophore-stimulated LTB₄ formation with an IC₅₀ = 20 nM. In zymosan-stimulated mouse peritoneal macrophages producing both LTC₄ and PGE₂, 47·Na showed 9000-fold selectivity for inhibition of LTC₄ (IC₅₀ = 0.16 nM) over PGE₂ (IC₅₀ = 1500 nM). Preliminary pharmacokinetic evaluation in rat and cynomolgus monkey demonstrated good oral bioavailability and elimination half-lives of 9 and 5 h, respectively. Pharmacological evaluation of leukotriene inhibition with oral dosing was demonstrated in a rat pleural inflammation model (ED₅₀ = 3 mg/kg) and a rat peritoneal passive anaphylaxis model (LTB₄, ED₅₀ = 2.5 mg/kg; LTE₄, ED₅₀ = 1.0 mg/kg). In a model of airway constriction induced by antigen challenge in actively sensitized guinea pigs, 47·Na dosed orally blocked bronchoconstriction with an ED₅₀ = 0.4 mg/kg, the most potent activity we have observed for any leukotriene inhibitor in this model. The mode of inhibitory action of 47·Na occurs at the stage of 5-lipoxygenase biosynthesis as it blocks both leukotriene pathways leading to LTB₄ and LTC₄ but not PGH₂ biosynthesis. However, 47·Na does not inhibit 5-lipoxygenase catalysis in a broken cell enzyme assay; therefore it is likely that 47·Na acts as a FLAP inhibitor.